Encephalitis is a collective term for acute, remittent or chronic neuroinflammatory diseases of the central nervous system (CNS) characterized by destruction of myelin sheaths, axonal damage, and neuronal injury or death. There are infectious and non-infectious or autoimmune forms of neuroinflammation. Prevalent examples of non-infectious neuroinflammation include Alzheimer's disease, Parkinson's disease, and multiple sclerosis (MS), while more rare forms include amyotrophic lateral sclerosis (ALS), and other chronic neurological disorders. Early pathological findings in the acute/subacute forms of MS point to the inflammation of the blood vessels within the neurovascular unit as the initial pathogenic event. Patients with neuroinflammation, including MS, exhibit permanent functional deficits associated with demyelination and lesion formation. While symptomatic MS patients exhibit some form of neurological deficit, there is variation in clinical presentation, disease course and pathological features. Temporal acute worsening of the symptoms in acute or remittent MS can be particularly devastating. Current treatments of such crises, including corticosteroids or interferon, are reasonably effective; however, some patients show little or no benefit. Despite this heterogeneity, one common feature of MS is blood brain barrier (BBB) disruption, which is linked to clinical relapse. The earliest events associated with BBB disruption is extravasation of immune cells, leakage of blood proteins and activation of microglia. Among the proteins that traverse into the CNS are factors of the blood coagulation cascade.
The pathogenesis of neuroinflammation has been linked to local activation of the coagulation system and deposition of fibrin. Blood vessel injuries are strong promoters of blood coagulation activation and thrombogenesis. Analysis of brain tissue from MS patients has revealed the presence of coagulation proteins, including deposition of fibrin, the product of thrombin mediated cleavage of fibrinogen, within MS lesions and around blood vessels. Among these coagulation proteins are procoagulant enzymes, tissue factor, protein C inhibitor, and fibrinogen. Fibrinogen is a classic acute-phase reactant, containing binding sites for cellular receptors regulating inflammatory processes. It is also a major substrate for the procoagulant serine protease thrombin. Administration of heparin, a direct inhibitor of thrombin, reduces the number of MS exacerbations, suggesting that anticoagulant treatment may be beneficial for MS therapy. Experimental models of neuroinflammation support this approach as either heparin or the direct thrombin inhibitor hirudin is beneficial in experimental autoimmune encephalomyelitis (EAE). Likewise, complementary studies performed in fibrinogen-deficient mice or fibrin depletion by prophylactic administration of anticoagulants or batroxobin have established that fibrin is at least one thrombin substrate that drives EAE disease progression and severity. To date, however, randomized controlled clinical studies have not been conducted to explore the use of anticoagulants to improve the outcome of neuroinflammatory disorders, including MS.
Activated protein C (APC) is a plasma serine protease with anticoagulant properties. APC is generated on the endothelial cell surface by the molecular complex of thrombomodulin and thrombin. In addition to reducing thrombin generation, APC functions as a signaling molecule, exhibiting cytoprotective, anti-inflammatory and anti-apoptotic effects via activation of the protease-activated receptor (PAR)-1 and endothelial protein C receptor (EPCR). In animal models, APC exerts beneficial effects during neuroinflammation in the CNS and periphery, suppressing pro-inflammatory NF-κB signaling and apoptosis in endothelial, neuronal and immune cell populations. Mutant APC analogs with reduced anticoagulant activity also exhibit neuroprotective properties in animal models of CNS injury. Indeed, the ability of exogenous APC administration to reduce neurological deficits and suppress neuroinflammation in the CNS and periphery in EAE indicates that augmenting this pathway may have therapeutic potential for neuroinflammatory disorders, including MS. However, exogenous APC (Drotecogin alfa) is no longer available for clinical evaluation.